Diagnosis and treatment of drug-resistant Ewing'S sarcoma

Abstract

Disclosed herein are diagnostic and prognostic methods for determining drug sensitivity and resistance in Ewing's sarcoma patients. Treatments for drug-resistant Ewing's sarcoma are also disclosed. The assays involve the detection of GSTM4 gene expression alone or in combination with other clinical factors. The tests are suitable for diagnosing and monitoring treatment of patients having or suspected of having Ewing's sarcoma. The disclosure also relates to inhibitors of GSTM4 for the treatment of Ewing's sarcoma, including drug-resistant forms thereof.

What is claimed is: 
     
       1. A method for determining a prognosis of a patient with Ewing's sarcoma, said method comprising:
 (a) determining the level of expression of a gene encoding glutathione S-transferase mu 4 (GSTM4) in a sample of Ewing's sarcoma cells acquired from the patient; and 
 (b) determining the patient has a relatively worse prognosis if the level of expression determined is equal to or greater than a reference level at or above which there is a statistically significant negative correlation between the level of expression of the gene in a sample of Ewing's sarcoma acquired from individuals and the individuals' overall survival; or 
 (c) determining the patient has a relatively better prognosis if the level of expression determined is less than a reference level at or above which there is a statistically significant negative correlation between the level of expression of the gene in Ewing's sarcomas acquired from individuals and the individuals' overall survival. 
 
     
     
       2. The method of  claim 1 , wherein the level of expression of a gene encoding GSTM4 in the sample is determined by measuring the amount of RNA encoding GSTM4. 
     
     
       3. The method of  claim 2 , wherein the amount of RNA encoding GSTM4 is measured after amplification of the RNA in the sample using reverse transcription-polymerase chain reaction (RT-PCR). 
     
     
       4. The method of  claim 2 , wherein the measurement of the amount of RNA in the sample employs a detectably labeled primer or probe. 
     
     
       5. The method of  claim 1 , wherein the level of expression of a gene encoding GSTM4 in the sample is determined by measuring the amount of GSTM4 protein. 
     
     
       6. The method of  claim 5 , wherein the amount of GSTM4 protein is measured using an immunoassay. 
     
     
       7. The method of  claim 6 , wherein said immunoassay is selected from the group consisting of an ELISA, a Western blot assay, and an immunohistochemical assay. 
     
     
       8. The method of  claim 1 , wherein said sample of Ewing's sarcoma cells acquired from the patient is acquired by biopsy. 
     
     
       9. The method of  claim 1 , wherein if the patient is determined to have a relatively worse prognosis the patient is more likely to have a relatively decreased overall survival as compared to a patient determined to have a relatively better prognosis. 
     
     
       10. The method of  claim 1 , wherein if the patient is determined to have a relatively better prognosis the patient is more likely to have a relatively increased overall survival as compared to a patient determined to have a relatively poor prognosis. 
     
     
       11. The method of  claim 1 , wherein if the patient is determined to have a relatively worse prognosis the patient is less likely to respond to treatment with a chemotherapeutic agent selected from etoposide and fenretinide. 
     
     
       12. The method of  claim 1 , wherein if the patient is determined to have a relatively better prognosis the patient is more likely to respond to treatment with a chemotherapeutic agent selected from etoposide and fenretinide.